Paternal activation of CB ₂ cannabinoid receptor impairs placental and embryonic growth via an epigenetic mechanism

Abstract

The cannabinoid receptor type 2 (CB ₂) is the peripheral receptor for cannabinoids, involved in the homeostatic control of several physiological functions. Male mitotic germ cells express a high level of CB ₂, whose activation promotes their differentiation in both in vitro and in vivo experiments, controlling the correct progression of spermatogenesis. However, it remains elusive if CB ₂ activation in spermatogonia could affect reproductive success in terms of fertility and healthy pregnancy outcomes. In this study, we explored the effects of male CB ₂ activation on sperm number and quality and its influence on next generation health. We show that exposure of male mice to JWH-133, a selective CB ₂ agonist, decreased sperm count, impaired placental development and reduced offspring growth. These defects were associated with altered DNA methylation/hydroxymethylation levels at imprinted genes in sperm and conserved in placenta. Our findings reveal that paternal selective activation of CB ₂ alters the sperm epigenome and compromises offspring growth. This study demonstrates, for the first time, a new role of CB ₂ signaling in male gametes in causing epigenetic alterations that can be transmitted to the next generation by sperm, highlighting potential risks induced by recreational cannabinoid exposure.